Is active surveillance appropriate for men with favorable intermediate-risk prostate cancer?

In a paper in the first issue of the new journal JAMA Oncology, a group of US-based researchers argue that data from a series of > 5,000 patients treated with first-line brachytherapy suggest that men with favorable intermediate-risk prostate cancer are actually good candidates for active surveillance.

The full text of this paper by Raldow et al. (with Dr. Anthony D’Amico as the senior author) examines detailed data from a prospective cohort of 5,580 men (median age, 67.50 years) who had localized adenocarcinoma of the prostate who were consecutively treated with brachytherapy at the Prostate Cancer Foundation of Chicago between October 16, 1997, and May 28, 2013.

So the first question we need to appreciate is what the authors mean by “favorable intermediate-risk prostate cancer.” This is defined with unquestionable clarity as follows:

  • A Gleason score of 3 + 3 = 6 or 3 + 4 = 7 and
  • A percentage of positive biopsy cores (PPBC) of < 50 percent and
  • At most one National Comprehensive Cancer Network (NCCN) determinant of intermediate-risk prostate cancer (which include a Gleason score of 7, a PSA level of 10 to 20 ng/ml, and a clinical stage of T2b or T2c)

Of the 5,580 patients enrolled in this cohort of patients, 3,972 met the NCCN criteria for low-risk disease and the remaining 1,608 met the criteria above for favorable intermediate-risk disease. (The details can be seen in Table 1 of the paper.)

In a studied analysis of the outcomes of the patients in this cohort, all of whom (we note again) were treated with brachytherapy alone as first-line treatment, Radlow et al. report that:

  • After median follow-up of 7.69 years,
    • 605/5,580 men (10.84 percent) had died of all causes
    • 34/5,580 men (0.61 percent) had died of prostate cancer (which equates to 5.62 of the 605 total deaths).
  • Compared to men with low-risk prostate cancer, men with favorable intermediate-risk prostate cancer had
    • No significant increase in risk of all-cause mortality (adjusted hazard ratio [aHR] = 1.11; P  = 0.380)
    • No significant increase in risk of prostate cancer-specific mortality (aHR = 1.64; P = 0.21)
  • The 8-year adjusted point estimates for all-cause mortality were
    • 10.45 percent for favorable men with intermediate-risk disease
    • 8.68 percent for men with low-risk disease
  • The 8-year adjusted point estimates for prostate cancer-specific mortality were
    • 0.48 percent for men with favorable intermediate-risk disease
    • 0.33 percent for men with low-risk disease

In other words, the authors argue that

Men with low-risk [prostate cancer] and favorable intermediate-risk [prostate cancer] have similarly low estimates of [prostate cancer-specific mortality] and [all-cause mortality] during the first decade following brachytherapy.

They then go on to argue further that,

  • Since all the men treated by brachytherapy who had NCCN low-risk disease should (according to the NCCN guidelines) have actually been managed initially on active surveillance, and
  • Since all the men treated by brachytherapy who had favorable intermediate-risk disease had 8-year outcomes similar to those of the men with NCCN low-risk disease, then
  • There is a reasonable argument that all men with favorable low-risk disease should also be managed initially on active surveillance.

Now if this paper hadn’t come from the source it did (with Dr. D’Amico as the senior author), one might have been tempted to ignore it, but

  • It is based on a large, consistent series of men all treated at a single institution over 15 years.
  • The analysis appears to have been conducted with a great deal of care and rigor.
  • The authors are very clear about the limitations of the study.

What Radlow et al. have laid out here is an hypothesis for which your Sitemaster has long had considerable sympathy … that many men with favorable intermediate-risk prostate cancer and a life expectancy of 10+ years are, in fact, perfectly reasonable candidates for active surveillance. We would note with care that this does not mean that we think they will all live out their lives with no need for any treatment. (We don’t think that Radlow et al. believe this either.) The point they are making is that some of these men would live out their lives with no need for any treatment at all for their prostate cancer; some may indeed go on to need first-line treatment in the next 10 years (and that treatment may still be able to place them in long-term remission, but deferred by a considerable period of time); and some will indeed still die of prostate cancer, but it will be a small percentage that may never have responded well to standard therapy a decade earlier anyway.

The primary reason for electing active surveillance as first-line management is to defer active, invasive therapy until it is actually needed (as opposed to having to accept the risk of complications and side effects of active treatment any earlier than one has to). Radlow et al.’s hypothesis is presented in that spirit: it may be perfectly reasonable to monitor favorable intermediate-risk prostate cancer for years before treatment is actually needed (if it ever is). This makes perfect sense to The “New” Prostate Cancer InfoLink, and (as Radlow et al. also note), proof of the correctness of their hypothesis may not be that far away … as we await the outcomes of the ProtecT trial in the UK, scheduled for 2016.

Since your Sitemaster is now 67 years of age, if he was diagnosed tomorrow with low-risk or favorable intermediate-risk prostate cancer as defined by Radlow et al. (and with a life expectancy of something like another 25 years based on family genealogy and his current state of health), he wishes to assure his readers that he has no doubt about what his first-line management strategy would be (albeit with annual multi-parametric MRIs as opposed to annual biopsies unless a follow-up biopsy was recommended by the MRI or other data).

4 Responses

  1. Sitemaster,

    Thank you for posting this review with the article link. We are of similar age and I share your desire to avoid RP if at all possible — if it can be done without jeopardizing one’s quality of life and longevity.

    If it were me facing this decision about AS vs primary treatment for intermediate prostate cancer ( and fortunately I am not), I would consider that the follow-up length of this study, 8 years, is just not long enough to help one plan one’s strategy. I think the differences in longevity with treatment vs AS for intermediate prostate cancer would become more apparent in the 10- to 15-year follow-up period. Having the goal of living an additional 10 years after age 67 when one is otherwise perfectly healthy would be cutting things shorter than need be, I would argue. (My mother is 96 and going strong in her own place.)

    Follow-up mp mri yearly with mri guided biopsies if needed at a place with good experience with mp mri would be a very good step for follow-up. I would also opt for genetic studies on the initial biopsy specimens, whether it be Polaris or something similar such as the genetic test being reported out of MD Anderson. Also, if the initial prostate biopsy pathology was done at a local hospital rather than an academic center, I would want the pathology report reviewed by an outside academic center.

    Everything that is being mentioned has been learned thanks to this website. It is very much appreciated that your viewers are permitted to participate in these discussions.

  2. Walter:

    You need to appreciate that my decision is not a decision about whether I can stay on AS for 10 years or longer. It is a decision about how long I can defer any form of invasive treatment. At 67 years of age, even 5 years of being able to avoid such treatment looks like a “good idea” to me, and (in my entirely personal opinion) comes with a distinctly low risk for future metastasis and prostate cancer-specific mortality — if one meets the specified criteria for favorable intermediate risk and one monitors the condition with care over time. On the other hand, of course, that decision is by no means “risk-free”.

  3. This paper and your analysis support a statement I believe I have heard Dr. Peter Carroll at UCSF make more than once –- that men properly selected and who follow active surveillance have no worse outcomes should they opt for treatment later than men with similar disease demographics who refused active surveillance and went straight to primary treatment.

  4. Sitemaster,

    You will shortly be seeing (and probably will comment on) the recent Sunnybrook 15-year study results of follow-up of intermediate-risk prostate cancer patients on active surveillance (AS). As one might have anticipated, the intermediate-risk AS patients did not do as well as the low-risk AS patients, having 3.7 times the risk of death; 11.5% died compared with 3.7% in the low-risk group.

    It goes without saying that anyone electing AS for intermediate-risk prostate cancer has got to be very careful and it may very well turn out that only a select few should consider AS if they have intermediate-risk disease.

    Thanks to the ongoing current literature reviews on this site, people will have a better idea on what kinds of things to ask for if they are considering AS for intermediate risk prostate cancer.

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